Li Ren-Yong, Kosugi Isao, Tsutsui Yoshihiro
Second Department of Pathology, Hamamatsu University School of Medicine, 1-20-1 Handayama, 431-3192 Hamamatsu, Japan.
Acta Neuropathol. 2004 May;107(5):406-12. doi: 10.1007/s00401-004-0828-0. Epub 2004 Mar 23.
Cytomegalovirus (CMV) is the most significant infectious cause of congenital infection and fatal diseases in immunocompromised patients. We have previously described a transgenic mouse model of the murine CMV (MCMV) immediate-early (IE) gene promoter fused with the lacZ reporter gene (MCMV-IE-pro1) for the analysis of spatiotemporal changes of the promoter activity during brain development. Since expression of the IE genes play a pivotal role in latency and reactivation, we transplanted the transgene-expressing neural stem cells (NSCs) into neonatal mouse brains after labeling with bromodeoxyuridine (BrdU). The activation of MCMV-IE pro1 was detected in the subventricular zone (SVZ) soon after transplantation, and the number of MCMV IE pro1-activated cells was decreased as the development proceeded. Cells that were MCMV IE pro1-activated and glial fibrillary acidic protein positive, but not stained with BrdU, were found in the cortex 4 weeks after transplantation, while BrdU-positive but not MCMV IE pro1-activated cells still existed in the SVZ. MCMV IE promoter activity tended to be easily detected in the cortex after allogenic transplantation in BALB/c mouse. These results suggest that the SVZ is the most susceptible site for activation of the MCMV IE promoter in neonatal mice in the early period after transplantation and that the cerebral cortex is also susceptible to the activation in the late period after transplantation. It may be important to avoid the use of NSCs latently infected with CMV as donor cells.
巨细胞病毒（CMV）是先天性感染以及免疫功能低下患者致命疾病的最主要感染病因。我们之前描述过一种转基因小鼠模型，该模型将鼠巨细胞病毒（MCMV）即刻早期（IE）基因启动子与lacZ报告基因融合（MCMV-IE-pro1），用于分析脑发育过程中启动子活性的时空变化。由于IE基因的表达在潜伏和再激活中起关键作用，我们在用溴脱氧尿苷（BrdU）标记后，将表达转基因的神经干细胞（NSCs）移植到新生小鼠脑中。移植后不久，在脑室下区（SVZ）检测到MCMV-IE pro1的激活，并且随着发育进行，MCMV IE pro1激活细胞的数量减少。移植4周后，在皮质中发现了MCMV IE pro1激活且胶质纤维酸性蛋白呈阳性但未被BrdU染色的细胞，而BrdU阳性但未被MCMV IE pro1激活的细胞仍存在于SVZ中。在BALB/c小鼠中进行同种异体移植后，MCMV IE启动子活性在皮质中往往更容易被检测到。这些结果表明，SVZ是移植后早期新生小鼠中MCMV IE启动子激活最敏感的部位，并且大脑皮质在移植后期也易受激活。避免使用潜伏感染CMV的NSCs作为供体细胞可能很重要。
